Leishmania parasites mainly infect macrophages and may cause severe immunopathologies in their host,which are called leishman-iases.In the current work,we infected human and mouse macrophages in vitro with Leishmania ...Leishmania parasites mainly infect macrophages and may cause severe immunopathologies in their host,which are called leishman-iases.In the current work,we infected human and mouse macrophages in vitro with Leishmania major,an etiological agent of cu-taneous leishmaniasis,and found that inhibition or deletion of the transforming growth factorβ–activated kinase 1(TAK1)gene re-sulted in increased parasite loads.In vivo,following a challenge with L.major,mice with a macrophage-specific deletion of TAK1 showed increased clinical signs and higher parasite loads compared with wild-type controls.TAK1 deficiency in mouse macro-phages led to biased Th2 cell responses during the acute stage of infection,characterized by a decrease in interferon-γexpression,and increased expression of IL-4,IL-5 and IL-10.Finally,we found that,in the late stage of L.major infection,excessive Th2-related cytokines led to high arginase 1 expression in mouse tissues and a significant reduction of NO production both locally and system-ically,resulting in compromised control of Leishmania.These findings suggest that TAK1 plays a vital role in host resistance to Leish-mania infection.展开更多
基金supported by grants from the Institute Pasteur International Direction,International Partnership Program(153831KYSB20190008)the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB29030303)+4 种基金the National Key Basic Research Program(2018YFA0507300,2022YFC2304700,2022YFC2303200)the National Natural Science Foundation of China(81830049,92269202)the Shanghai Municipal Science and Technology Major Project(#2019SHZDZX02)the Research Leader Program(#20XD1403900)the Innovation Capacity Building Project of Jiangsu province(BM2020019)。
文摘Leishmania parasites mainly infect macrophages and may cause severe immunopathologies in their host,which are called leishman-iases.In the current work,we infected human and mouse macrophages in vitro with Leishmania major,an etiological agent of cu-taneous leishmaniasis,and found that inhibition or deletion of the transforming growth factorβ–activated kinase 1(TAK1)gene re-sulted in increased parasite loads.In vivo,following a challenge with L.major,mice with a macrophage-specific deletion of TAK1 showed increased clinical signs and higher parasite loads compared with wild-type controls.TAK1 deficiency in mouse macro-phages led to biased Th2 cell responses during the acute stage of infection,characterized by a decrease in interferon-γexpression,and increased expression of IL-4,IL-5 and IL-10.Finally,we found that,in the late stage of L.major infection,excessive Th2-related cytokines led to high arginase 1 expression in mouse tissues and a significant reduction of NO production both locally and system-ically,resulting in compromised control of Leishmania.These findings suggest that TAK1 plays a vital role in host resistance to Leish-mania infection.
